BASIC NUTRITIONAL INVESTIGATION Nutrition Vol. 15, No. 2, 1999 Dietary Amino Acids as New and Novel Agents to Enhance Allograft Survival J. WESLEY ALEXANDER, MD, SCD,*² JOHN F. VALENTE, MD,* NORMAN A. GREENBERG, PHD‡, DAVID A. CUSTER, AS,* CORA K. OGLE, PHD,*² SCOTT GIBSON, MD,* AND GEORGE BABCOCK, PHD*² From the *Department of Surgery, University of Cincinnati Medical Center, Cincinnati, Ohio; the ²Shriners Burns Institute, Cincinnati, Ohio; and the ‡Novartis Nutrition Technical Center, St. Louis Park, Minnesota, USA Date accepted: 9 March 1998 ABSTRACT Dietary supplementation with arginine was previously found to enhance cardiac allograft survival in rats when given with a donor-specific transfusion and a short low-dose course of cyclosporine. This study was performed to determine further the role of amino acid supplementation in prolonging allograft survival. Standard isocaloric, isonitrogenous diets were modified to contain 2 or 4% of energy from arginine, 2 or 4% from glutamine, 4% from glycine or the following combinations: 2% arginine with 2% glutamine, 2% arginine with 4% glutamine, or 1% arginine with 2% glutamine. These diets were started along with a donor-specific transfusion and a 7-d course of cyclosporine the day before cardiac transplantation from an ACI to Lewis strain rat. Median survival times in days for the groups were as follows: control without amino acids, 19.0; 2% arginine, 68.0; 4% arginine, 35.5; 2% glutamine, 28.5; 4% glutamine, 53.5; 4% glycine, 31.5; 2% arginine with 2% glutamine, 39.5; 2% arginine with 4% glutamine, 42.5 and 1% arginine with 2% glutamine, 35.5. Each experimental diet except 2% glutamine and 4% glycine significantly enhanced allograft survival (P  0.05) with the 2% arginine diet being the best (91.6  32.3 d [mean  SEM] versus 20.1  3.2 d for control). It is concluded that both arginine and glutamine enhance the immunosuppressive effects of donor-specific transfusion and cyclosporine. Nutrition 1999;15:130 –134. ©Elsevier Science Inc. 1999 Key words: transplantation, immunosuppression, arginine, glutamine, immunonutrient INTRODUCTION Immunonutrients can be defined as nutrients found in nat- ural food sources that have pharmacologic effects on the im- mune system when given in amounts in excess of that required to maintain good health. The immunonutrients that have been found to have the greatest effects on immune responses are the long-chain fatty acids, especially of the -3 series, the amino acids arginine, glutamine, and glycine and, to a lesser extent, vitamins that have antioxidant effects including vitamins E, C, and A, and the minerals selenium and zinc. Complete enteral formulations containing various combinations of immunonutri- ents have been used clinically to prevent infections and lessen inflammatory responses with beneficial clinical effects in well- controlled, prospectively randomized, placebo-controlled dou- ble-blind studies. 1 One of these formulations, Impact (Novartis Nutrition, Min- neapolis, MN), when given as the sole source of nutrients, was found to greatly enhance cardiac allograft survival in rats receiv- ing a donor-specific transfusion (DST) and a short course of cyclosporine A (CsA). 2 The animals given a DST and a 14-d course of low-dose CsA had a mean allograft survival of 72  7d when fed a regular rodent chow compared with 275  5 d when given Impact as their sole source of nutrition (P  0.015). Be- cause Impact includes fish oil and arginine as the major immu- nonutrients, a subsequent study (unpublished data) was done with a standardized AIN-76A diet that was modified to include either 10% of energy from fish oil, 2% from arginine, or 5% from Presented as a poster at the 16th meeting of the American Society of Transplant Physicians, May 10 –14, 1997, Chicago, Illinois, USA. Supported by a grant from Novartis Nutrition, Minneapolis, Minnesota, USA, and the Cincinnati Shriners Burns Institute. Correspondence to: J. Wesley Alexander, MD, Department of Surgery, University of Cincinnati Medical Center, Cincinnati, OH 45267-0558, USA. E-mail: alexanjw@healthall.com Nutrition 15:130 –134, 1999 ©Elsevier Science Inc. 1999 0899-9007/99/$20.00 Printed in the USA. All rights reserved. PII S0899-9007(98)00169-5